Summary: Dr. Rudy Castellani of the University of Maryland has received the 2010 Journal of Alzheimer’s Disease outstanding contribution award for his article criticizing the popular hypothesis that a protein called beta amyloid causes Alzheimer’s. The award highlights the growing disagreement about the causes of Alzheimer’s.
Alzheimer’s is caused by plaques and tangles in the brain, right? Wrong, says a group of researchers who believe that focusing on these abnormal proteins is keeping scientists from investigating other potential causes.
In a 2009 article in the Journal of Alzheimer’s Disease, they wrote that the popular hypothesis that beta amyloid (the protein found in plaques) causes dementia is flawed. This flawed hypothesis is why potential Alzheimer’s drugs continue to fail in clinical trials, they said, and has caused unnecessary suffering for patients and families.
Last month, the 300+ Associate Editors of the Journal of Alzheimer’s Disease voted to give Dr. Rudy Castellani, the lead author of this article, the Journal’s annual award for outstanding contribution. The award highlights the growing disagreement about the causes of Alzheimer’s.
Dr. Castellani is Professor of Pathology and Director of Neuropathology at the University of Maryland. The two Editors-in-Chief of the journal, Mark Smith and George Perry, are co-authors of the paper, and with Dr. Castellani, have long hypothesized that events earlier in the disease process, not beta amyloid, cause Alzheimer’s. Their logic goes something like this:
Alzheimer’s is caused by plaques and tangles in the brain, right? Wrong, says a group of researchers who believe that focusing on these abnormal proteins is keeping scientists from investigating other potential causes.
In a 2009 article in the Journal of Alzheimer’s Disease, they wrote that the popular hypothesis that beta amyloid (the protein found in plaques) causes dementia is flawed. This flawed hypothesis is why potential Alzheimer’s drugs continue to fail in clinical trials, they said, and has caused unnecessary suffering for patients and families.
Rudy J. Castellani, Jr., MD
Last month, the 300+ Associate Editors of the Journal of Alzheimer’s Disease voted to give Dr. Rudy Castellani, the lead author of this article, the Journal’s annual award for outstanding contribution. The award highlights the growing disagreement about the causes of Alzheimer’s.
Dr. Castellani is Professor of Pathology and Director of Neuropathology at the University of Maryland. The two Editors-in-Chief of the journal, Mark Smith and George Perry, are co-authors of the paper, and with Dr. Castellani, have long hypothesized that events earlier in the disease process, not beta amyloid, cause Alzheimer’s. Their logic goes something like this:
- Abnormal accumulations of beta amyloid (the protein in plaques) and tau (the protein in tangles) are not harmful, and are simply end-stage signs of earlier problems
- Recent research indicates that beta amyloid may be protective – a normal immune response and an anti-oxidant
- The accumulation of beta amyloid that can be seen at autopsy (and on new brains scans) is not well correlated with dementia
- The focus on these abnormal proteins has crowded out funding needed to research other hypotheses.
Still the Main Hypothesis, At Least in Public
Dr. Castellani and his co-authors are not alone in their thinking. In the five years I’ve been blogging, many researchers have privately told me they think the amyloid hypothesis is wrong and that Alzheimer’s research is headed in the wrong direction. In the last couple of years, this discussion has become more open at research and public events (a webcast event at the University of Pennsylvania and ICAD 2008, for example). So why is the amyloid hypothesis still the main theory in Alzheimer’s research?
“Based on my interaction with various neuroscientists and clinicians in the field, the dominant hypothesis -- the so-called amyloid cascade, now the synaptic abeta hypothesis -- is widely viewed as seriously flawed,” says Dr. Castellani. “Unfortunately, there is a lot of money and associated influence, as well as prestigious names and titles with a personal stake in the ultimate success of treatment efforts modeled after their preferred construct. Alzheimer’s research involves selling ideas as much as (and more in my view) objective pursuit of knowledge. In this respect, the peer review process is a bit of a farce, as it encourages fealty to existing ideas and hampers innovation, in spite of unending lip service paid to the latter.”
And if there are doubts about the amyloid hypothesis, why do presentations and articles about Alzheimer’s for a lay audience often present it as fact? “The popular press (major media outlets, many of them) will run articles, with or without schematic representations, along with quotes from esteemed researchers at the world’s top institutions,” says Dr. Castellani. “They speak of (overly simplistic) removal of bad proteins, the exciting results from (hopelessly irrelevant) experimental models, economic burdens to society if something isn’t done, anecdotal accounts of human intervention, etc, etc. All this, which taken together amounts to no more than snake oil in terms of a cure, permeates public thought and pretty soon everyone wants to be vaccinated [against beta amyloid]. Lost in the process is a hypothesis that is deeply flawed and certainly unproven.”
A Lot at Stake
The amyloid hypothesis, right or wrong, is important because a large number of potential Alzheimer’s treatments are based on it. If it’s wrong, the hopes of patients and families will continue to be dashed, and millions of dollars will have been wasted on drug development. [It seems ironic that the cash prize associated with the award Dr. Castellani received is sponsored by Elan Pharmaceuticals, which is developing potential Alzheimer’s treatments based on the amyloid hypothesis.]
If it’s wrong, people enrolled in clinical trials of amyloid-lowering treatments are being subjected to unnecessary risk. In addition, looking for ways to prevent or treat Alzheimer’s by studying people with the rare early onset familial form of Alzheimer’s might not be useful. These patients inherit genetic variations that alter the way beta amyloid is processed, but their illness is not really the same as most Alzheimer’s, Dr. Castellani and colleagues write. Two such efforts are DIAN and the Alzheimer’s Prevention Initiative described in a recent New York Times article.
Finally, if the amyloid hypothesis is wrong, then new brain scans that can measure amounts of amyloid aren’t useful, and in fact may falsely diagnose someone with Alzheimer’s. This would make efforts to detect “preclinical Alzheimer’s disease” difficult.
If Not Amyloid, Then What?
So if the amyloid hypothesis is wrong, where should Alzheimer’s scientists focus? Dr. Castellani argues for starting over with a much broader approach. “I think we have to throw the kitchen sink at the problem,” he says. “Everything should be on the table, including a poly-therapy approach that encompasses multiple constructs and hypotheses.”
Starting over sounds discouraging, but Dr. Castellani seems confident that scientists will eventually find the cause of Alzheimer’s, if only because of a lucky break. “The proof will be in the pudding,” he says. “Sooner or later, there will be a breakthrough, and it will be by accident. At that point, the time and effort will be devoted to elucidating a mechanism that explains the accident, as the change in accepted science will have occurred by the force of empiricism.”
Dr. Castellani and his co-authors are not alone in their thinking. In the five years I’ve been blogging, many researchers have privately told me they think the amyloid hypothesis is wrong and that Alzheimer’s research is headed in the wrong direction. In the last couple of years, this discussion has become more open at research and public events (a webcast event at the University of Pennsylvania and ICAD 2008, for example). So why is the amyloid hypothesis still the main theory in Alzheimer’s research?
“Based on my interaction with various neuroscientists and clinicians in the field, the dominant hypothesis -- the so-called amyloid cascade, now the synaptic abeta hypothesis -- is widely viewed as seriously flawed,” says Dr. Castellani. “Unfortunately, there is a lot of money and associated influence, as well as prestigious names and titles with a personal stake in the ultimate success of treatment efforts modeled after their preferred construct. Alzheimer’s research involves selling ideas as much as (and more in my view) objective pursuit of knowledge. In this respect, the peer review process is a bit of a farce, as it encourages fealty to existing ideas and hampers innovation, in spite of unending lip service paid to the latter.”
And if there are doubts about the amyloid hypothesis, why do presentations and articles about Alzheimer’s for a lay audience often present it as fact? “The popular press (major media outlets, many of them) will run articles, with or without schematic representations, along with quotes from esteemed researchers at the world’s top institutions,” says Dr. Castellani. “They speak of (overly simplistic) removal of bad proteins, the exciting results from (hopelessly irrelevant) experimental models, economic burdens to society if something isn’t done, anecdotal accounts of human intervention, etc, etc. All this, which taken together amounts to no more than snake oil in terms of a cure, permeates public thought and pretty soon everyone wants to be vaccinated [against beta amyloid]. Lost in the process is a hypothesis that is deeply flawed and certainly unproven.”
A Lot at Stake
The amyloid hypothesis, right or wrong, is important because a large number of potential Alzheimer’s treatments are based on it. If it’s wrong, the hopes of patients and families will continue to be dashed, and millions of dollars will have been wasted on drug development. [It seems ironic that the cash prize associated with the award Dr. Castellani received is sponsored by Elan Pharmaceuticals, which is developing potential Alzheimer’s treatments based on the amyloid hypothesis.]
If it’s wrong, people enrolled in clinical trials of amyloid-lowering treatments are being subjected to unnecessary risk. In addition, looking for ways to prevent or treat Alzheimer’s by studying people with the rare early onset familial form of Alzheimer’s might not be useful. These patients inherit genetic variations that alter the way beta amyloid is processed, but their illness is not really the same as most Alzheimer’s, Dr. Castellani and colleagues write. Two such efforts are DIAN and the Alzheimer’s Prevention Initiative described in a recent New York Times article.
Finally, if the amyloid hypothesis is wrong, then new brain scans that can measure amounts of amyloid aren’t useful, and in fact may falsely diagnose someone with Alzheimer’s. This would make efforts to detect “preclinical Alzheimer’s disease” difficult.
If Not Amyloid, Then What?
So if the amyloid hypothesis is wrong, where should Alzheimer’s scientists focus? Dr. Castellani argues for starting over with a much broader approach. “I think we have to throw the kitchen sink at the problem,” he says. “Everything should be on the table, including a poly-therapy approach that encompasses multiple constructs and hypotheses.”
Starting over sounds discouraging, but Dr. Castellani seems confident that scientists will eventually find the cause of Alzheimer’s, if only because of a lucky break. “The proof will be in the pudding,” he says. “Sooner or later, there will be a breakthrough, and it will be by accident. At that point, the time and effort will be devoted to elucidating a mechanism that explains the accident, as the change in accepted science will have occurred by the force of empiricism.”
Mona, this is a fantastic article. I hope it doesn't sound immodest to say that the field is slowly beginning to support the arguments we set out in The Myth of Alzheimer's in 2008. Good to see credible researchers like Rudy, George, and others being forthright about the challenges we face.
Posted by: Danny George | June 07, 2010 at 06:59 PM
Hello
And so now we are spending billions based on the premise that eventually "luck" not science, not a growing consesus will lead to a "cure."
A cure for what? What does it mean to cure a generalized disorder(s) of the brain? How is a chronic long term disability cured? reversed? slowed down?
There are so many more basic questions to which answers must be found before we (researchers and drug companies) know were is the best place to start to get "lucky."
This is much more than a debate between self-employer researchers. The unintended consequences of their exaggerations, over/miss representations and claims become the basis for, the reason to hope that tomorrow will be better than today for folks living with the symptoms of dementia, probably of the alzheimer's type.
And another issue - everyone with dementia does not exhibit the same general pattern of symptoms labeled for lack of a better word as Alzheimer's Disease. Raising money, focusing almost exclusively to "break through" what ever the hell the Alzheimer's Association thinks needs broken through ignores the needs of as many as half the folks living with dementia.
And another issues. When I was diagnosed the general claim was 40-50% of thos living with dementia probably had the alzheimer's type. REcently I saw a claim that percentage has escelated to 60-80%. Could there be a conscious effort to crowd out the needs of many in order to raise funds to research the needs of a few?
And another issue. Why spend these limited funds almost exclusively on bench/pill/cure research and ignore the psycho-social research needs of those living with the disease.
Must people living with the symptoms organize and represent themselves and their needs? Can we depend on others to think and act in our best interests - especially those who are invested in alzheimer's and the fear of getting it, having it, or having to take care of someone who has it - as the basis upon which they raise money?
"A world without Alzheimer"" We may be living in such a world right now! And won't someone(s) be embarassed when most of agree this is true - except for fund raisers, researchers, and drug companies.
Richard
www.richardtaylorphd.com
Posted by: Richard Taylor | June 08, 2010 at 11:43 AM
Thanks for this.
I am especially pleased to see that his peers have supported Dr.Castellani's research. There is new hope.
Posted by: Oran | June 09, 2010 at 04:30 PM
In light of the failure of so many drugs trials, it's important to re-think the whole question of AD. There is serious doubt about the amyloid and senile plaque hypothesis. In 2006 I wrote an article at the BBC h2g2 website in which I presented a new line of thinking about the disease. The site address is: www.bbc.co.uk/dna/h2g2/brunel/A17484203
Posted by: Robert Nield | January 28, 2011 at 01:10 PM